Nutritional composition for use in therapy of cancer patients

ABSTRACT

The invention relates to PUFA, vitamin E, vitamin D and the protein bound amino acids glycine, arginine and tryptophan as active ingredients for use in therapy of cancer patients, wherein an effective amount of said active ingredients is administered in the form of a nutritional composition comprising a) a lipid component providing 40-50 EN % based on the total energy of the nutritional composition, wherein 12-16 EN % based on the total energy of the nutritional composition is provided by PUFA, b) 4.0-8.0 mg/100 mL alpha-TE vitamin E, c) 5.0-12.0 μg/100 mL vitamin D, d) 2.5-4.5 g/100 mL glycine, e) 0.5-1.5 g/100 mL arginine, and f) at least 0.02 g/100 mL tryptophan.

FIELD OF THE INVENTION

The invention relates to PUFA, vitamin E, vitamin D and the proteinbound amino acids glycine, arginine and tryptophan as active ingredientsfor use in therapy of cancer patients, wherein an effective amount ofsaid active ingredients is administered in the form of a nutritionalcomposition. The invention also relates to the nutritional compositionas such.

BACKGROUND OF THE INVENTION

Weight loss and malnutrition occur frequently in patients with cancer.It is well established that weight loss and malnutrition lead to pooreroutcomes for cancer patients. This includes decreased functional status,increased complication rates and a detrimental effect on quality oflife. Overall, this leads to an increase in morbidity and mortality.

Cancer patients are frequently found to be malnourished at the time ofdiagnosis and, depending on the site and stage of the tumor, they havefrequently lost weight prior to their diagnosis. Weight loss arisesearly in the course of disease and is a prominent feature throughout thepatient's cancer journey (disease, anticancer treatment and recovery).

Nutritional intake and nutritional status of cancer patients can beimpaired by a multitude of reasons including decreased nutritionalintake, the patient's response to the tumor causing anorexia (e.g.,early satiety, reduced appetite), physical abnormalities associated withthe tumor (e.g., altered metabolism, increased catabolism) as well asside effects of the cancer treatments themselves (e.g., nausea,constipation, diarrhea, extensive resection with loss of functionalcapacity, mucositis, stomatitis, dysphagia). Another important factorwhen considering oral intake is the emotional effect both the diagnosisand treatment can have on a patient (e.g., depression, grief, anxiety,pain).

Cancer is a chronic condition often identified late and it involvescomplex multimodal treatment. To survive and grow, tumors transform hoststores into their energy fuel, thus affecting host metabolism andnutritional status even before it becomes clinically evident. Inresponse the host produces a number of specific immune-derived factorsin a futile attempt to isolate, starve, and kill the tumor cells. Thisaltered metabolism can lead to anorexia, malnutrition, and eventuallycachexia.

Cancer cachexia is a multifactorial syndrome characterized by an ongoingloss of skeletal muscle mass (with or without loss of fat mass). Cancercachexia causes functional impairment and is prevalent in the majorityof cancer patients. Cachexia leads to weight loss, muscle mass lossand/or a reduced response to treatment and ultimately causes prematuremortality.

Side effects that have been associated with malnutrition and cachexia incancer patients include poor prognosis, increased risk of complicationsin surgery and radiotherapy, impaired response to chemotherapy, fatigue,decreased performance status and/or diminished ability to toleratetreatment.

Due to on-going treatment, energy requirements for cancer patients areunlikely to be met with food alone. Energy requirements can also behigher due to the altered metabolism. The protein requirements forcancer patients are increased due to the loss of lean body mass causedby the altered metabolism. Furthermore, cancer patients are often notable to meet their micronutrient (e.g. vitamin D) requirements with foodalone. To ensure these requirements are met, nutritional compositions,in particular oral nutritional compositions, are needed.

Accordingly, there is a need for systems which can be used in therapy ofcancer patients. In particular, there is a need for nutritionalcompositions which provide sufficient amounts of calories, protein andmicronutrients (e.g. vitamin D) in a relatively low volume, as cancerpatients do often not tolerate high or even normal volumes of foodand/or nutritional compositions. Preferably, such compositions can beadapted to be nutritionally complete.

SUMMARY OF THE INVENTION

The inventors found a system which can be used in therapy of cancerpatients. Said system involves the combined use of PUFA, vitamin E,vitamin D and the protein bound amino acids glycine, arginine andtryptophan as active ingredients. The corresponding nutritionalcompositions provide sufficient amounts of calories, protein andmicronutrients (e.g. vitamin D) in a relatively low volume, and they canbe adapted to be nutritionally complete.

Accordingly, in a first aspect, the present disclosure relates to PUFA,vitamin E, vitamin D and the protein bound amino acids glycine, arginineand tryptophan as active ingredients for use in therapy of cancerpatients, wherein an effective amount of said active ingredients isadministered in the form of a nutritional composition comprising a) alipid component providing 40-50 EN % based on the total energy of thenutritional composition, wherein 12-16 EN % based on the total energy ofthe nutritional composition is provided by PUFA, b) 4.0-8.0 mg/100 mLalpha-TE vitamin E, c) 5.0-12.0 μg/100 mL vitamin D, d) 2.5-4.5 g/100 mLglycine, e) 0.5-1.5 g/100 mL arginine, and f) at least 0.02 g/100 mLtryptophan.

In a second aspect, the present disclosure relates to the nutritionalcomposition as such.

In a third aspect, the present disclosure relates to a dose unitcomprising the nutritional composition.

In a fourth aspect, the present disclosure relates to a dosage regimefor use in (nutritional) therapy of cancer patients.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“High protein” as used herein refers to nutritional compositions whereinthe protein component provides at least 15 EN %, preferably at least 18EN %, more preferably at least 19 EN %, most preferred at least 20 EN %based on the total energy of the nutritional composition. In preferredembodiments, such nutritional compositions comprise at least 10 wt %,preferably at least 12 wt %, more preferably at least 13 wt %, mostpreferred at least 14 wt % of protein based on the total weight of thenutritional composition. According to the present disclosure, there maybe an upper limit to protein content, for example at most 40 EN %,preferably at most 30 EN %, more preferably at most 28 EN %.

“High caloric” as used herein refers to nutritional compositions havinga caloric density of at least 2 kcal/mL, preferably at least 2.5kcal/ml, more preferably at least 2.8 kcal/mL, most preferably at least3.0 kcal/mL.

“Nutritional composition” herein refers to a synthetically produced foodcomposition. Thus, nutritional compositions are artificial nutritionalproducts obtained by mixing/dissolving bulk ingredients whereby saidingredients are typically provided in solid form (e.g. powders) orliquid from (e.g. oils, water, syrup). The term “nutritionalcomposition” excludes “food”, i.e. non-modified natural food products,such as meat, vegetables, fruits in their natural form andconventionally prepared (e.g. cooked) meals or drinks like tea, coffeeor juices.

For the present disclosure, “nutritional compositions” are limited toliquid or semi-solid compositions.

“Patient nutrition” as used herein refers to nutrition intended forindividuals suffering from a medical condition. Patient nutrition asdefined herein excludes the provision of nutrients in the form ofconventionally prepared meals (“food”). Patient nutrition therefore onlyrefers to the provision of nutrients in form of nutritional compositionsas defined above. Herein, patient nutrition is intended for patientshaving high caloric needs and high protein needs.

“Nutritionally complete” refers to nutritional compositions suitable assole source of nutrition. To be nutritionally complete, it is requiredthat a nutritional composition comprises—in addition to the lipid,carbohydrate and protein components—minerals and vitamins. In order tobe nutritionally complete, vitamins and minerals should be present insufficient amounts as known to the man skilled in the art, i.e. inaccordance with established nutritional guidelines. The recommendednutrient requirements, in particular with respect to minerals andvitamins, can be found in standard nutritional guidelines such as EUcommission directive 1999/21/EC (see tables 2 and 3 hereinbelow).Suitable nutrients according to the present disclosure fulfil therequirements of/are listed in REGULATION (EU) No 609/2013.

“Malnutrition” as used herein refers to one or both of Option I: bodymass index (BMI, kg/m2)<18.5; Option II: the combined finding ofunintentional weight loss (mandatory) and at least one of either reducedBMI or a low fat free mass index (FFMI). Weight loss is defined aseither >10% of habitual weight indefinite of time, or >5% over 3 months.Reduced BMI is <20 or <22 kg/m2 in subjects younger and older than 70years, respectively. Low FFMI is <15 and <17 kg/m2 in females and males,respectively.

The term “(nutritional) therapy” as used herein refers to therapy,preferably nutritional therapy.

A composition “consisting of” a number of ingredients or components isto be understood as comprising no other than the named ingredients orcomponents. In case ranges for amounts of ingredients or components aregiven, the individual amount of all ingredients or components within thecomposition has of course also to be adapted such that the sum of allamounts of all present ingredients or components adds up to 100 wt %.

“Homogenization” as used herein refers to the process of diminishing thesize of the fat globules in a nutritional emulsion. A preferredhomogenization process herein comprises two homogenization steps. Thefirst homogenization step may be carried out at a pressure of 100 barand the second homogenization step may be carried out at a pressure of50 bar. Both steps may be carried out at a temperature of 60-80° C.,such as 65-75° C., for example 65° C.

“UHT-treatment” aims at killing of microorganisms. Preferred UHTtreatment may be carried out with a pre-heat treatment at 90° C. for 3min followed by UHT at 139° C. for 6 seconds, followed by a (third)homogenization step requiring homogenization at less than 90° C. with apressure that can oscillate between 40-150 bar.

The term “protein bound amino acid” is known to a person skilled in theart. As a person skilled in the art is aware of, a protein is composedof amino acids. Protein bound amino acids are the amino acids which theprotein is composed of. In other words, a protein bound amino acid is anamino acid which is bound in a protein. Accordingly, a free amino acidis not a protein bound amino acid. The term “protein” as used in theterm “protein bound amino acid” preferably refers to a protein having anaverage molecular weight (M_(w)) of ≥500 Da, preferably ≥800 Da, morepreferably ≥1000 Da. The term “protein” as used in the term “proteinbound amino acid” preferably refers to a protein having an averagemolecular weight (M_(w)) of ≤100 kDa, preferably ≤80 kDa, morepreferably ≤60 kDa. In particularly preferred embodiments, the aminoacids are bound in collagen hydrolysate or milk protein. One advantageof the use of protein bound amino acids over free amino acids is theimproved taste associated therewith.

“Protein component” as used herein refers to the entirety of ingredientsof the nutritional composition declarable as “protein”.

“Hydrolysed collagen” or “collagen hydrolysate” as used herein refers tolow molecular weight collagen obtainable by hydrolysis of collagen byprocedures known to the skilled artisan. Embodiments of hydrolysedcollagen as preferred herein have an average molecular weight M_(w) offrom 1000 Da to 6000 Da, preferably 1000 to 3000 Da. Methods fordetermining the average molecular weight are well known in the art. Anexemplary method is given hereinbelow.

“Lipid component” as used herein refers to the entirety of ingredientsof the nutritional composition declarable as “fat”. The term “PUFA” asused herein refers to polyunsaturated fatty acids. The term“omega-6-PUFA” as used herein refers to omega-6-polyunsaturated fattyacids. The term “omega-3-PUFA” as used herein refers toomega-3-polyunsaturated fatty acids. The term “MUFA” as used hereinrefers to monounsaturated fatty acids. The term “SFA” as used hereinrefers to saturated fatty acids.

“Carbohydrate component” as used herein refers to the entirety ofingredients of the nutritional composition declarable as “carbohydrate”.

“EN %” refers to the contribution of a certain component or of aspecific ingredient to the total nutritional energy of an ediblecomposition, e.g. the nutritional composition.

“Ready-to-use” refers to the final form of the nutritional compositionas administered to a patient. Typically, the nutritional compositionsherein are pre-packed in a ready to use format, i.e. sold in separatelypacked dose units that do not require any further dilution etc.

If not specified otherwise, the expression “/100 mL” as used hereinmeans “per 100 mL of the nutritional composition”. For example, if notspecified otherwise, the expression “g/100 mL” as used herein refers to“g per 100 mL of the nutritional composition”, the expression “mg/100mL” as used herein refers to “mg per 100 mL of the nutritionalcomposition”, and the expression “μg/100 mL” as used herein refers to“μg per 100 mL of the nutritional composition”, etc.

Nutritional Compositions

The nutritional compositions herein comprise nutrients in predeterminedand controllable amounts. A nutritional composition according to thepresent disclosure comprises a protein component, a lipid component andvitamins. Optionally, such a nutritional composition may furthercomprise a carbohydrate component. Optionally, such a nutritionalcomposition may further comprise minerals. Optionally, such anutritional composition may further comprise dietary fibres and/orfurther ingredients known as food additives. In particularly preferredembodiments, such a nutritional composition further comprises water.

Preferably, the nutritional compositions have a high caloric density.Also preferably, the nutritional compositions have a high proteincontent. Particularly preferably, the nutritional compositions have ahigh caloric density and a high protein content.

Typically, the nutritional compositions have a caloric density of atleast 2.0 kcal/mL, preferably at least 2.5 kcal/mL, more preferably atleast 2.6 kcal/mL, even more preferably at least 2.8 kcal/mL, even morepreferably at least 3.0 kcal/mL, even more preferably at least 3.1kcal/mL. Typically, the nutritional compositions have a caloric densityof at most 5.0 kcal/mL, preferably at most 4.0 kcal/mL, more preferablyat most 3.8 kcal/mL, even more preferably at most 3.6 kcal/mL, even morepreferably at most 3.4 kcal/mL, even more preferably at most 3.3kcal/mL. Preferably, the nutritional compositions have a caloric densityof 2.0-5.0 kcal/mL, preferably 2.5-4.0 kcal/mL, more preferably 2.6-3.8kcal/mL, even more preferably 2.8-3.6 kcal/mL, even more preferably3.0-3.4 kcal/mL, even more preferably 3.1-3.3 kcal/mL. Particularpreference is also given to nutritional compositions having a caloricdensity of 3.0-4.0 kcal/mL.

The nutritional compositions herein may comprise a protein component, alipid component, a carbohydrate component, wherein

-   -   a. the protein component provides at least 15 EN %, preferably        at least 18 EN %, more preferably at least 19 EN % based on the        total energy of the nutritional composition;    -   b. the lipid component provides 40-50 EN % based on the total        energy of the nutritional composition;    -   c. the carbohydrate component provides at least 20 EN % based on        the total energy of the nutritional composition.

Preferably, the nutritional compositions according to the presentdisclosure comprise a protein component, a lipid component, acarbohydrate component, wherein

-   -   a. the protein component provides 15-25 EN %, preferably 18-22        EN %, more preferably 19-21 EN % based on the total energy of        the nutritional composition;    -   b. the lipid component provides 40-50 EN %, preferably 43-47 EN        %, more preferably 44-46 EN % based on the total energy of the        nutritional composition; and    -   c. the carbohydrate component provides 30-40 EN %, preferably        33-37 EN %, more preferably 34-36 EN % based on the total energy        of the nutritional composition.

In preferred embodiments, the nutritional compositions herein comprise40-60 wt %, preferably 45-55 wt % of water based on the total weight ofthe nutritional composition. In preferred embodiments, the nutritionalcompositions herein comprise 45-65 vol %, preferably 50-60 vol % ofwater based on the total volume of the nutritional composition.

The nutritional compositions typically are liquid or semi-solid. Inpreferred embodiments, the nutritional composition is an emulsion. Inparticularly preferred embodiments, the nutritional composition is anoil-in-water (O/W) emulsion.

Preferably, the nutritional composition of the present disclosure isnutritionally complete.

Preferably, the nutritional composition of the present disclosure is aready to use nutritional composition.

The nutritional composition of the present disclosure is administeredenterally, preferably orally.

The nutritional composition of the invention shows good tolerability andpalatability resulting in excellent compliance. Good compliance isimportant because it helps to increase a patient's total protein andenergy intake.

In preferred embodiments, the nutritional composition herein comprisesthe following components in the following amounts:

Embodiment I Embodiment II Protein: 19-21 EN % 20 EN % Collagenhydrolysate 80%  16 g/100 mL Milk protein 20% glycine* 3.2-3.7 g/100 mL3.42 g/100 mL arginine* 0.9-1.2 g/100 mL 1.05 g/100 mL tryptophan*0.04-0.07 g/100 mL  0.05 g/100 mL proline* 2.2-2.6 g/100 mL 2.38 g/100mL cysteine* 0.02-0.05 g/100 mL  0.03 g/100 mL Fat: 44-46 EN % 45 EN %Rapeseed oil  16 g/100 mL of which SFA  2-4 EN %  3 EN %  1.1 g/100 mLof which MUFA 26-30 EN % 28 EN %  9.9 g/100 mL of which PUFA 13-15 EN %14 EN %  5.0 g/100 mL CHO 34-36 EN % 35 EN %  28 g/100 mL Caloricdensity 3.1-3.3 kcal/mL, 3.2 kcal/mL preferably 3.2 kcal/mL Water 50-60mL/100 mL  56 mL/100 mL  FSMP balanced ** yes yes Vitamin D3 7.5-8.5μg/100 mL   8 μg/100 mL Vitamin E 5.5-6.0 mg/100 mL  5.67 mg/100 mL (alpha-TE) (alpha-TE) *Bound in collagen hydrolysate or milk protein **Nutritionally complete in vitamins and minerals

In more preferred embodiments, the nutritional composition hereincomprises the following components in the following amounts:

Embodiment III Embodiment IV Protein: 19-21 EN % 20 EN % Collagenhydrolysate 80%  16 g/100 mL Milk protein 20% glycine* 3.2-3.7 g/100 mL3.42 g/100 mL arginine* 0.9-1.2 g/100 mL 1.05 g/100 mL tryptophan*0.04-0.07 g/100 mL  0.05 g/100 mL proline* 2.2-2.6 g/100 mL 2.38 g/100mL cysteine* 0.02-0.05 g/100 mL  0.03 g/100 mL Fat: 44-46 EN % 45 EN %Rapeseed oil  16 g/100 mL of which SFA  2-4 EN %  3 EN %  1.1 g/100 mLof which MUFA 26-30 EN % 28 EN %  9.9 g/100 mL of which PUFA 13-15 EN %14 EN %  5.0 g/100 mL CHO 34-36 EN % 35 EN %  28 g/100 mL Caloricdensity 3.1-3.3 kcal/mL, 3.2 kcal/mL preferably 3.2 kcal/mL Water 50-60mL/100 mL  56 mL/100 mL  FSMP balanced ** yes yes Calcium 150-175 mg/100mL   160 mg/100 mL  Zinc 3.0-4.0 mg/100 mL  3.5 mg/100 mL  Copper480-540 μg/100 mL  512 μg/100 mL  Selenium 20-25 μg/100 mL  23 μg/100 mLVitamin D3 7.5-8.5 μg/100 mL   8 μg/100 mL Vitamin E 5.5-6.0 mg/100 mL 5.67 mg/100 mL  (alpha-TE) (alpha-TE) Vitamin B6 0.55-0.62 mg/100 mL   0.58 mg/100 mL  Vitamin B12 1.0-1.2 μg/100 mL  1.1 μg/100 mL Folic acid60-75 μg/100 mL 67.2 μg/100 mL  Vitamin C 35-50 mg/100 mL  41.6 mg/100mL  *Bound in collagen hydrolysate or milk protein ** Nutritionallycomplete in vitamins and minerals

In even more preferred embodiments, the nutritional composition hereincomprises the following components in the following amounts:

Embodiment V Embodiment VI Protein: 19-21 EN % 20 EN % Collagenhydrolysate 80%   16 g/100 mL Milk protein 20% glycine* 3.2-3.7 g/100 mL 3.42 g/100 mL arginine* 0.9-1.2 g/100 mL  1.05 g/100 mL tryptophan*0.04-0.07 g/100 mL   0.05 g/100 mL proline* 2.2-2.6 g/100 mL  2.38 g/100mL cysteine* 0.02-0.05 g/100 mL   0.03 g/100 mL Fat: 44-46 EN % 45 EN %Rapeseed oil   16 g/100 mL of which SFA  2-4 EN %  3 EN %  1.1 g/100 mLof which MUFA 26-30 EN % 28 EN %  9.9 g/100 mL of which PUFA 13-15 EN %14 EN %  5.0 g/100 mL CHO 34-36 EN % 35 EN %   28 g/100 mL Caloricdensity 3.1-3.3 kcal/mL, 3.2 kcal/mL preferably 3.2 kcal/mL Water 50-60mL/100 mL   56 mL/100 mL FSMP balanced ** yes yes Sodium 100-125 mg/100mL   112 mg/100 mL Potassium 290-340 mg/100 mL   312 mg/100 mL Chloride130-160 mg/100 mL   144 mg/100 mL Calcium 150-175 mg/100 mL   160 mg/100mL Magnesium 35-45 mg/100 mL   40 mg/100 mL Phosphorus 100-125 mg/100mL   112 mg/100 mL Iron 4.3-5.2 mg/100 mL   4.8 mg/100 mL Zinc 3.0-4.0mg/100 mL   3.5 mg/100 mL Copper 480-540 μg/100 mL   512 μg/100 mLManganese 0.9-1.5 mg/100 mL   1.2 mg/100 mL Iodide 40-50 μg/100 mL 44.8μg/100 mL Fluoride 0.35-0.45 mg/100 mL      0.4 mg/100 mL Chromium 20-25μg/100 mL  23 μg/100 mL Molybdenum 27-35 μg/100 mL 30.4 μg/100 mLSelenium 20-25 μg/100 mL  23 μg/100 mL Vitamin A 200-250 μg/100 mL   224μg/100 mL (RE***) (RE***) Beta-Carotene 400-450 μg/100 mL   426 μg/100mL Vitamin D3 7.5-8.5 μg/100 mL    8 μg/100 mL Vitamin E 5.5-6.0 mg/100mL  5.67 mg/100 mL  (alpha-TE) (alpha-TE) Vitamin K1 17-25 μg/100 mL20.8 μg/100 mL Vitamin B1 0.45-0.55 mg/100 mL      0.5 mg/100 mL VitaminB2 0.47-0.55 mg/100 mL     0.51 mg/100 mL  Niacin 5.0-5.8 mg/100 mL  5.4 mg/100 mL Vitamin B6 0.55-0.62 mg/100 mL     0.58 mg/100 mL Vitamin B12 1.0-1.2 μg/100 mL   1.1 μg/100 mL Pantothenic acid 1.80-2.10mg/100 mL     1.92 mg/100 mL  Biotin 13.0-16.0 μg/100 mL    14.4 μg/100mL Folic acid 60-75 μg/100 mL 67.2 μg/100 mL Vitamin C 35-50 mg/100 mL 41.6 mg/100 mL  *Bound in collagen hydrolysate or milk protein **Nutritionally complete in vitamins and minerals ***Retinol equivalents

Protein Component

The invention involves the use of the protein bound amino acids glycine,arginine and tryptophan. Accordingly, the nutritional composition hereincomprises a protein component.

According to the invention, the nutritional composition comprises2.5-4.5 g/100 mL glycine. Typically, the nutritional compositioncomprises 3.0-4.0 g/100 mL glycine, preferably 3.2-3.7 g/100 mL glycine.Preferably, at least 80 mol %, more preferably at least 90 mol %, evenmore preferably at least 95 mol %, even more preferably at least 98 mol%, most preferably at least 99 mol % of the glycine comprised in thenutritional composition is protein bound. Glycine promotes the synthesisof creatine in the body, which helps to build lean muscle mass and raiseenergy levels in the muscles by synthesizing muscle protein increasingnitrogen retention.

According to the invention, the nutritional composition comprises0.5-1.5 g/100 mL arginine. Typically, the nutritional compositioncomprises 0.8-1.3 g/100 mL arginine, preferably 0.9-1.2 g/100 mLarginine. Preferably, at least 80 mol %, more preferably at least 90 mol%, even more preferably at least 95 mol %, even more preferably at least98 mol %, most preferably at least 99 mol % of the arginine comprised inthe nutritional composition is protein bound. Arginine promotes creatinesynthesis in the body, which supports muscle metabolism by maintaining ahealthy nitrogen balance, which helps to increase muscle mass.

According to the invention, the nutritional composition comprises atleast 0.02 g/100 mL tryptophan. Typically, the nutritional compositioncomprises 0.02-0.2 g/100 mL tryptophan, preferably 0.03-0.1 g/100 mLtryptophan, more preferably 0.04-0.07 g/100 mL tryptophan. Preferably,at least 80 mol %, more preferably at least 90 mol %, even morepreferably at least 95 mol %, even more preferably at least 98 mol %,most preferably at least 99 mol % of the tryptophan comprised in thenutritional composition is protein bound. Tryptophan is an indispensableamino acid, which helps to ensure normal protein metabolism.

Optionally, the nutritional composition further comprises proline,preferably 1.5-4.0 g/100 mL proline, more preferably 2.0-3.0 g/100 mLproline, even more preferably 2.2-2.6 g/100 mL proline. Preferably, atleast 80 mol %, more preferably at least 90 mol %, even more preferablyat least 95 mol %, even more preferably at least 98 mol %, mostpreferably at least 99 mol % of the proline optionally comprised in thenutritional composition is protein bound.

Optionally, the nutritional composition further comprises cysteine,preferably at least 0.01 g/100 mL cysteine, more preferably 0.01-0.1g/100 mL cysteine, even more preferably 0.02-0.05 g/100 mL cysteine.Preferably, at least 80 mol %, more preferably at least 90 mol %, evenmore preferably at least 95 mol %, even more preferably at least 98 mol%, most preferably at least 99 mol % of the cysteine optionallycomprised in the nutritional composition is protein bound.

In preferred embodiments, the protein component comprises collagen orhydrolysed collagen. In particularly preferred embodiments, the proteincomponent comprises hydrolysed collagen. In other preferred embodiments,the protein component comprises collagen. In other preferredembodiments, the protein component comprises collagen and hydrolysedcollagen.

In preferred embodiments, the protein component comprises a proteinsource selected from vegetable proteins, animal proteins other thancollagen and mixtures thereof, for example milk protein, soy protein,pea protein, egg white and hydrolysates thereof. In preferredembodiments, the protein component comprises a protein source selectedfrom milk proteins, such as total milk protein, milk protein isolate,milk protein concentrate, whey, casein and mixtures thereof.

In preferred embodiments, the protein component comprises collagen orcollagen hydrolysate as (a) protein source(s) and milk protein as aprotein source. In particularly preferred embodiments, the proteincomponent comprises collagen hydrolysate as a first protein source andmilk protein as a second protein source. In other preferred embodiments,the protein component comprises collagen as a first protein source andmilk protein as a second protein source. In other preferred embodiments,the protein component comprises collagen, collagen hydrolysate and milkprotein as protein sources.

Preferably, the protein component comprises at least two differentprotein sources. More preferably, the protein component comprises atleast two different protein sources, wherein the first protein source ishydrolysed collagen. In even more preferred embodiments, the proteincomponent comprises at least two different protein sources, wherein thefirst protein source is hydrolysed collagen and represents at least 35wt %, preferably 45-95 wt %, more preferably 55-90 wt %, even morepreferably 70-90 wt %, most preferably 80-85 wt % based on the totalweight of the protein component.

In particularly preferred embodiments, the protein component essentiallyconsists of collagen hydrolysate and milk protein. In particularlypreferred embodiments, the protein component consists of collagenhydrolysate and milk protein.

Comparing nutritional compositions comprising high amounts of hydrolysedprotein, the nutritional compositions comprising hydrolysed collagen(which are according to preferred embodiments of the invention) shouldlead to improved patient compliance due to improved rheological andsensorial properties like viscosity, texture and/or taste.

In preferred embodiments, the second protein source is selected fromvegetable proteins, animal proteins other than collagen and mixturesthereof, for example milk protein, soy protein, pea protein, egg whiteand hydrolysates thereof. In more preferred embodiments, the secondprotein source is selected from milk proteins, such as total milkprotein, milk protein isolate, milk protein concentrate, whey, caseinand mixtures thereof. A particularly preferred second protein source ismilk protein, e.g. total milk protein and/or milk protein concentrate.

Within the second protein source, proteins having different averagemolecular weights may be used. Preferred average molecular weights(M_(w)) of the proteins used within the second protein source lie in therange of 20-60 kDa. In such a range properties of the nutritionalcomposition can be well balanced in terms of heat stability and/orviscosity.

For example, a second protein source comprising a high amount of aprotein having a lower molecular weight will lead to a reduced viscosityof the nutritional composition. Therefore, a preferred second proteinsource comprises more than 40 wt %, preferably more than 50 wt % of aprotein having an average molecular weight of less than 40 kDa, such as20-40 kDa (based on the total weight of the second protein source).

A preferred protein component comprises collagen hydrolysate as thefirst protein source and milk protein as the second protein source. Sucha protein component is particularly suitable as it can be adapted suchthat it provides an amino acid distribution suitable to meet currentinternational recommendations for daily intake (e.g. when thenutritional compositions of the present disclosure are used as solesource of nutrition), even without addition of free amino acids, di- ortripeptides. Such an exemplary international recommendation has beenpublished by the WHO (Technical Report Series 935, 2007, p. 150).Particularly preferred is a protein component comprising 70-90 wt % ofhydrolysed collagen as the first protein source and 30-10 wt % milkprotein as the second protein source, such as 80 wt % hydrolysedcollagen with 20 wt % milk protein (each based on the total weight ofthe protein component).

Further amino acids may as well contribute to the protein component,preferably the second protein source. These may be added in theirchemical form or in the form of low molecular peptides, such as di- ortripeptides. However, in preferred embodiments neither free amino acidsnor di- or tripeptides are added to the protein component describedherein.

Nutritional compositions herein typically comprise at least 10 wt %,preferably at least 12 wt %, more preferably at least 13 wt % of proteinbased on the total weight of the nutritional composition.

Nutritional compositions herein typically comprise at least 14 g,preferably at least 15 g, more preferably at least 15.5 g, mostpreferably at least 16 g of protein per 100 mL of the nutritionalcomposition. Nutritional compositions herein typically comprise at most20 g, preferably at most 18 g, more preferably at most 17.0 g of proteinper 100 mL of the nutritional composition. Preferably, nutritionalcompositions herein comprise 14-20 g, more preferably 15-18 g, mostpreferably 15.5-17.0 g of protein per 100 mL of the nutritionalcomposition.

In preferred embodiments, the protein component provides at least 15 EN%, preferably at least 18 EN %, more preferably at least 19 EN % basedon the total energy of the nutritional composition. For example, theprotein component provides 15-25 EN %, preferably 18-22 EN %, morepreferably 19-21 EN % based on the total energy of the nutritionalcomposition.

Preferably, the protein to water ratio of the present nutritionalcomposition is at least 2.0/10 [g/g], more preferably at least 2.5/10[g/g].

As described above, the collagen hydrolysate, which is used in preferredembodiments of the invention, preferably has an average molecular weightM_(w) of from 1000 Da to 6000 Da, more preferably 1000 to 3000 Da.Examples are known to a person skilled in the art and commerciallyavailable (e.g. via Gelita, Germany). Such hydrolysates and methods formaking them are for example described in DE 102010060564 A1, inparticular par. [0004]-[0011] and Example 1 with the low molecularweight hydrolysates in par. [0030] being particularly suitable. Ofcourse, other sources than porcine gelatin can be used, with bovinebeing particularly preferred for the applications herein.

Accordingly, particularly preferred collagen hydrolysates have molecularweight distributions as listed below:

Mol. weight range Upper limit >7500 Da 10 wt % >3500-7500 Da 35 wt% >1500-3500 Da 35 wt % >500-1500 Da 50 wt % <500 Da 15 wt %

Particularly Mol. weight range Preferred range preferred range Example AExample B >7500 Da ≤10 wt % ≤5 wt % ≤5 wt % ≤5 wt % >3500-7500 Da 10-35wt % 10-20 wt % 10-20 wt % 12-18 wt % >1500-3500 Da 20-35 wt % 25-32 wt% 25-32 wt % 25-31 wt % >500-1500 Da 30-50 wt % 40-50 wt % 40-50 wt %40-46 wt % <500 Da ≤15 wt % ≤15 wt % ≤15 wt % 5-10 wt %

Preferably, at most 10 wt %, more preferably at most 5 wt % of thecollagen hydrolysate has a molecular weight of above 7,500 Da.

Preferably, at most 15 wt %, more preferably at most 5 wt % of thecollagen hydrolysate has a molecular weight of below 500 Da.

Thus, particularly preferred collagen hydrolysates are characterized byat least 75 wt %, preferably at least 90 wt % falling into the molecularweight range of 500-7500 Da.

Lipid Component

The nutritional composition herein comprises a lipid component. Saidlipid component may comprise one or more lipid sources, such as lipidsof animal and/or vegetable origin. Suitable lipid sources may beselected from oil of marine origin vegetable oils and combinationsthereof. Preferably, lipid sources may be selected from fish oil,sunflower oil, safflower oil, soy oil, rapeseed oil, canola oil, linseedoil and combinations thereof. Additionally, the lipid component maycomprise MCT in oil or fat form providing C6-C12 fatty acids.

In preferred embodiments, the lipid component comprises rapeseed oiland/or canola oil, preferably rapeseed oil, also preferably canola oil.

In one embodiment, the lipid component comprises fish oil. In anotherembodiment, the lipid component comprises rapeseed oil and fish oil. Inanother embodiment, the lipid component comprises canola oil and fishoil.

In terms of individual fatty acids, the lipid component typicallyincludes polyunsaturated fatty acids, monounsaturated fatty acids andsaturated fatty acids. Suitable fatty acids may be selected from thegroup consisting of caproic acid (C6:0), caprylic acid (C8:0), capricacid (C10:0), lauric acid (C12:0), myristic acid (C14:0), palmitic acid(C16:0), palmitoleic acid (C16:1w7), stearic acid (C18:0), oleic acid(C18:1w9), linoleic acid (C18:2w6), a-linolenic acid (C18:3w3),eicosapentaenoic acid (C20:5w3), docosahexaenoic acid (C22:6w3) andmixtures thereof. Particularly preferred fatty acids are linoleic acid,alpha-linolenic acid and mixtures thereof.

Fat is a rich source of energy which is invaluable when meeting apatient's nutritional requirements especially in a small volume. Itsupports the absorption of fat-soluble vitamins, such as vitamins D andE.

In the nutritional composition of the invention, the percentage energyfrom fat is higher than the current global nutrition societyrecommendations for an optimal fat supply in the healthy population.Such higher percentage energy from fat is, however, not contraindicatedin the malnourished population. In populations with inadequate totalenergy intake, dietary fats are an important macronutrient to increaseenergy intake to appropriate levels. The fat content in the presentnutritional composition is appropriate for the malnourished population.

PUFA are a concentrated source of energy and have many benefits. Forexample, replacing SFA by PUFA reduces the risk of coronary heartdisease (CHD). The risk of metabolic syndrome components and diabetescan be reduced as well.

In the nutritional composition of the invention, the percentage energyfrom PUFA is higher than the WHO recommendation. This recommendation isrelated to low tocopherol (vitamin E) intake. The main risk in a highertotal PUFA dietary intake is thought to be an increased risk of lipidperoxidation. The present nutritional composition provides vitamin E insufficient amounts, which will not only help the patients to meet theirvitamin E requirements but may also further reduce the impact or risk oflipid peroxidation. The PUFA content in the present nutritionalcomposition is appropriate for the malnourished population due to theneed for a positive energy balance to promote weight gain in a smallvolume.

According to the invention, the lipid component provides 40-50 EN %based on the total energy of the nutritional composition. Preferably,the lipid component provides 43-47 EN %, more preferably 44-46 EN %based on the total energy of the nutritional composition.

According to the invention, 12-16 EN % based on the total energy of thenutritional composition is provided by PUFA. Preferably, 13-15 EN %based on the total energy of the nutritional composition is provided byPUFA.

In preferred embodiments, 8-12 EN %, preferably 8.5-10.5 EN % based onthe total energy of the nutritional composition is provided byomega-6-PUFA. An example of an omega-6-PUFA is linoleic acid. Inpreferred embodiments, 3-5 EN %, preferably 3.5-5.0 EN % based on thetotal energy of the nutritional composition is provided by omega-3-PUFA.An example of an omega-3-PUFA is alpha-linolenic acid. Preferably, theratio [g/g] of omega-6-PUFA to omega-3-PUFA is 1.6-4.0, more preferably1.7-3.0.

In preferred embodiments, 24-32 EN %, preferably 26-30 EN %, for example28 EN %, based on the total energy of the nutritional composition isprovided by MUFA. In preferred embodiments, 1-5 EN %, preferably 2-4 EN%, for example 3 EN %, based on the total energy of the nutritionalcomposition is provided by SFA.

Carbohydrate Component

The nutritional composition herein may comprise a carbohydratecomponent. Said carbohydrate component may comprise one or morecarbohydrate sources. Typical carbohydrate sources may be selected fromthe group consisting of maltodextrine, glucose syrup, sucrose, fructose,isomaltulose, starch (modified or unmodified), tapioca dextrine, andmixtures thereof.

Typically, the carbohydrate component provides at least 20 EN %,preferably 30-40 EN %, more preferably 33-37 EN %, for example 34-36 EN% based on the total energy of the nutritional composition.

A preferred carbohydrate component comprises glucose syrup and,preferably sucrose. The carbohydrate component may comprise 65-95 wt %of glucose syrup and 5-35 wt % of sucrose based on the total weight ofthe carbohydrate component. Preferably, the carbohydrate componentcomprises 60-80 wt % glucose syrup and 20-40 wt % sucrose, for example65-75 wt % glucose syrup and 25-35 wt % sucrose based on the totalweight of the carbohydrate component.

Vitamins and Minerals

To be regarded as nutritionally complete, nutritional compositions haveto comprise vitamins and minerals.

Suitable vitamins to be included in the composition in order to renderit nutritionally complete according to the present disclosure areVitamin A, Vitamin D, Vitamin K, Vitamin C, Thiamin, Riboflavin, VitaminB6, Niacin, Folic acid, Vitamin B12, Pantothenic acid, Biotin andVitamin E. An example for rendering a nutritional composition completein vitamins is given in table 2.

Suitable minerals to be included in the composition in order to renderit nutritionally complete according to the present disclosure areSodium, Chloride, Potassium, Calcium, Phosphorus, Magnesium, Iron, Zinc,Copper, Iodine, Selenium, Manganese, Chromium and Molybdenum.Optionally, Fluoride may be included. An example for rendering anutritional composition complete in minerals is given in table 3.

According to the invention, the nutritional composition comprises4.0-8.0 mg/100 mL alpha-TE vitamin E. Typically, the nutritionalcomposition comprises 4.5-7.0 mg/100 mL alpha-TE vitamin E, preferably5.0-6.5 mg/100 mL alpha-TE vitamin E, more preferably 5.2-6.2 mg/100 mLalpha-TE vitamin E, even more preferably 5.5-6.0 mg/100 mL alpha-TEvitamin E. The term “alpha-TE” used in connection with vitamin E refersto alpha-tocopherol equivalents. Vitamin E helps to further reduce theimpact or risk of lipid peroxidation. Furthermore, vitamin E hasantioxidant properties and, thus, may protect tissue from oxidativedamage.

According to the invention, the nutritional composition comprises5.0-12.0 μg/100 mL vitamin D. Typically, the nutritional compositioncomprises 6.0-10.5 μg/100 mL vitamin D, preferably 7.0-9.5 μg/100 mLvitamin D, more preferably 7.2-9.0 μg/100 mL vitamin D, even morepreferably 7.5-8.5 μg/100 mL vitamin D. The term “vitamin D” as usedherein preferably refers to vitamin D3. Vitamin D modulates intestinalcalcium absorption and calcium release from bone, as well as renalphosphate excretion in order to maintain plasma calcium and phosphateconcentrations in a range supporting cellular processes, neuromuscularfunction, and bone ossification. Above its role in bone metabolism,vitamin D has additional extra-skeletal influences on the cardiovascularsystem, the endocrine system, the immune system and the nervous system.Benefits associated with adequate vitamin D levels include improvementsin bone health and skeletal muscle function, prevention or reduced riskof falls, fractures and osteoporosis as well as lower mortality. Anadequate intake of vitamin D in conjunction with high protein intakehelps to increase muscle mass.

Optionally, the nutritional composition further comprises B vitamins,preferably at least 5 mg/100 mL B vitamins, more preferably 6-20 mg/100mL B vitamins, even more preferably 7-12 mg/100 mL B vitamins. Examplesof B vitamins are vitamin B1, vitamin B2, niacin, vitamin B6, vitaminB12, pantothenic acid, biotin and folic acid. In preferred embodiments,the nutritional composition comprises vitamin B6, vitamin B12 and folicacid. In particularly preferred embodiments, the nutritional compositioncomprises vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12,pantothenic acid, biotin and folic acid. B vitamins, in particularvitamin B6, vitamin B12 and folic acid, help to improvecognitive/psychological function and to decrease cardiovascular risk.

Optionally, the nutritional composition further comprises vitamin B6,preferably 0.3-1.0 mg/100 mL vitamin B6, more preferably 0.5-0.7 mg/100mL vitamin B6, even more preferably 0.55-0.62 mg/100 mL vitamin B6.Optionally, the nutritional composition further comprises vitamin B12,preferably 0.6-2.0 μg/100 mL vitamin B12, more preferably 0.8-1.5 μg/100mL vitamin B12, even more preferably 1.0-1.2 μg/100 mL vitamin B12.Optionally, the nutritional composition further comprises folic acid,preferably 40-100 μg/100 mL folic acid, more preferably 50-85 μg/100 mLfolic acid, even more preferably 60-75 μg/100 mL folic acid.

Optionally, the nutritional composition further comprises vitamin C,preferably 20-80 mg/100 mL vitamin C, more preferably 30-60 mg/100 mLvitamin C, even more preferably 35-50 mg/100 mL vitamin C.

Optionally, the nutritional composition further comprises calcium,preferably 50-300 mg/100 mL calcium, more preferably 120-200 mg/100 mLcalcium, even more preferably 150-175 mg/100 mL calcium. Calcium, inparticular in combination with vitamin D, helps to improve bone healthand to reduce the risk of bone fragility, osteoporosis and bonefracture.

Optionally, the nutritional composition further comprises zinc,preferably 2.0-5.0 mg/100 mL zinc, more preferably 2.5-4.5 mg/100 mLzinc, even more preferably 3.0-4.0 mg/100 mL zinc.

Optionally, the nutritional composition further comprises copper,preferably 400-600 μg/100 mL copper, more preferably 450-570 μg/100 mLcopper, even more preferably 480-540 μg/100 mL copper.

Optionally, the nutritional composition further comprises selenium,preferably 10-40 μg/100 mL selenium, more preferably 15-30 μg/100 mLselenium, even more preferably 20-25 μg/100 mL selenium.

In one embodiment, the nutritional composition further comprises vitaminB6, vitamin B12, folic acid, copper and selenium, preferably in theamounts specified above.

In one embodiment, the nutritional composition further comprises vitaminC and zinc, preferably in the amounts specified above.

Fibre

The nutritional composition herein may comprise ingredients declarableas dietary fibres. Suitable dietary fibres may be selected from thegroup consisting of cocoa powder, inulin, wheat dextrine, cellulose,microcrystalline cellulose, soy polysaccharides, tapioca dextrine,xanthan, fructooligosaccharides, galactooligosaccharides, at leastpartially hydrolysed guar gum, acacia gum, pectin, oat fibre,polydextrose, resistant starch, hemicellulose and mixtures thereof

Additives

Nutritional compositions optionally comprise food additives. Additivesare typically present in total amount of less than 10 wt %, 5 wt % oreven less than 1 wt % based on the total weight of the nutritionalcomposition. Exemplary additives are choline, beta-carotene, lutein,lycopene, caffeine, lecithin, taurine, carnitine, myo-inositol,colorants, aroma and mixtures thereof. Aromas may be caramel, vanilla,yoghurt, chocolate, coffee, cappuccino, fruit aromas and the like.

The additives may include stabilisers and emulsifiers. Preferably, thestabilisers are selected from gums and mixtures thereof. For example,microcrystalline cellulose (E460), sodium carboxymethylcellulose (E466),carrageenan (E407), diacteyl tartaric acid ester of glycerides,cellulose gel (cellulose, microcrystalline) can be used. The emulsifiersmay be selected from (destilled) monoglycerides such as E471, soylecithins. For example, stabilizers and emulsifiers are included in thefollowing amounts/ratios monoglycerides (E471, as an emulsifier) 1-5 g/Land a stabilizer mixture comprising 0.3-5 g/L, soy lecithin 1-5 g/L,diacetyl tartaric acid of glycerides (E472, eg. DATEM) 0.1-5 g/L and MCC1-8 g/L.

Use in Therapy

According to the invention, the nutritional composition is used intherapy of cancer patients. In preferred embodiments, therapy refers tonutritional therapy. In preferred embodiments, the nutritionalcomposition is used as patient nutrition.

If not specified otherwise, the term “patient(s)” as used in the contextof the present invention refers to cancer patient(s).

Preferred cancer patients may have a low body mass index (BMI). Forexample, preferred cancer patients have a BMI of <22 kg/m2, preferably<20 kg/m2, more preferably <18.5 kg/m2, even more preferably <17 kg/m2,even more preferably <16 kg/m2.

Preferred cancer patients have a BMI of <22 kg/m2, preferably <20 kg/m2,more preferably <18.5 kg/m2, even more preferably <17 kg/m2, if they are70 years or older, and a BMI of <20 kg/m2, preferably <18.5 kg/m2, morepreferably <17 kg/m2, even more preferably <16 kg/m2, if they areyounger than 70 years.

Preferred cancer patients may have a low fat free mass index (FFMI).Preferred cancer patients have an FFMI of <16 kg/m2, preferably <15kg/m2, more preferably <14 kg/m2, even more preferably <13 kg/m2, ifthey are female, and an FFMI of <18 kg/m2, preferably <17 kg/m2, morepreferably <16 kg/m2, even more preferably <15 kg/m2, if they are male.

Particularly preferred cancer patients may have a low body mass index(BMI) and a low fat free mass index (FFMI). Particularly preferredcancer patients have a BMI of <22 kg/m2, preferably <20 kg/m2, morepreferably <18.5 kg/m2, even more preferably <17 kg/m2, if they are 70years or older, and a BMI of <20 kg/m2, preferably <18.5 kg/m2, morepreferably <17 kg/m2, even more preferably <16 kg/m2, if they areyounger than 70 years, and an FFMI of <16 kg/m2, preferably <15 kg/m2,more preferably <14 kg/m2, even more preferably <13 kg/m2, if they arefemale, and an FFMI of <18 kg/m2, preferably <17 kg/m2, more preferably<16 kg/m2, even more preferably <15 kg/m2, if they are male.

The cancer patients can be at any age. For example, the cancer patientsare 3 years or older, preferably 14 years or older, more preferably 18years or older. For example, the cancer patients are 25 years or older,or 30 years or older, or 40 years or older, or 50 years or older, or 60years or older, or 70 years or older. The cancer patients can, forexample, be at home or in a nursing home, a hospital or a hospice.

The cancer can be any cancer. Preferably, the cancer is selected fromthe group consisting of gastrointestinal cancer, pancreatic cancer,esophageal cancer, stomach cancer, kidney cancer, bladder cancer, headand neck cancer, ovarian cancer, uterine cancer, lung cancer, colorectalcancer, haematological cancer, liver cancer, gallbladder cancer, breastcancer and prostate cancer. More preferably, the cancer is selected fromthe group consisting of gastrointestinal cancer, pancreatic cancer,esophageal cancer, stomach cancer, kidney cancer, bladder cancer, headand neck cancer, ovarian cancer, uterine cancer, lung cancer, colorectalcancer and haematological cancer. Even more preferably, the cancer isselected from the group consisting of gastrointestinal cancer,pancreatic cancer, esophageal cancer, stomach cancer, kidney cancer andbladder cancer. Also even more preferably, the cancer is head and neckcancer or haematological cancer. Particularly preferably, the cancer isgastrointestinal cancer or head and neck cancer, preferablygastrointestinal cancer, also preferably head and neck cancer.

In one preferred embodiment, the nutritional composition is used in theprevention or treatment of malnutrition, preferably proteinmalnutrition, also preferably protein-energy malnutrition (PEM).

In one preferred embodiment, the nutritional composition is used in theprevention or treatment of nutrient deficiencies associated withmalnutrition, preferably protein malnutrition, also preferablyprotein-energy malnutrition (PEM).

In one preferred embodiment, the nutritional composition is used in(nutritional) therapy of cancer patients which suffer from anorexia,cachexia and/or sarcopenia and/or which are pre-cachexic and/orpre-sarcopenic. In another preferred embodiment, the nutritionalcomposition is used in (nutritional) therapy of cancer patients whichsuffer from anorexia, cachexia and/or sarcopenia.

In a particularly preferred embodiment, the nutritional composition isused in (nutritional) therapy of cancer patients which suffer fromanorexia.

In a particularly preferred embodiment, the nutritional composition isused in (nutritional) therapy of cancer patients which suffer fromcachexia or which are pre-cachexic, preferably cancer patients whichsuffer from cachexia, also preferably cancer patients which arepre-cachexic.

In a particularly preferred embodiment, the nutritional composition isused in (nutritional) therapy of cancer patients which suffer fromsarcopenia or which are pre-sarcopenic, preferably cancer patients whichsuffer from sarcopenia. Sarcopenia frequently occurs in cancer patients.Sarcopenia as used herein refers to the loss of muscle mass and functionor to the loss of muscle mass and strength, preferably to the loss ofmuscle mass, muscle function and muscle strength.

Preferably, the nutritional composition to be administered is providedin a dose unit of 100-200 mL, more preferably 100-150 mL. Alsopreferably, the nutritional composition to be administered is providedin a dose unit providing 300-500 kcal, more preferably 350-450 kcal.Also preferably, the nutritional composition to be administered isprovided in a dose unit providing 15-30 g, more preferably 18-22 g ofprotein. Particularly preferably, the nutritional composition to beadministered is provided in a dose unit of 125 mL providing 400 kcal and20 g of protein.

Preferably, the nutritional composition is administered in 3-8 doseunits daily, preferably 5 dose units daily, for example 5 dose unitsdaily each providing 350-450 kcal, or for example 5 dose units dailyeach providing 18-22 g of protein. Also preferably, the nutritionalcomposition is administered in 1-3 dose units daily, preferably 1 or 2dose units daily, for example 1 or 2 dose units daily each providing350-450 kcal, or for example 1 or 2 dose units daily each providing18-22 g of protein.

In preferred embodiments, the nutritional composition is administered ina daily dose of 1500-2500 kcal or in a daily dose of 75-125 g ofprotein. Such daily doses are particularly suitable for completenutrition. In other preferred embodiments, the nutritional compositionis administered in a daily dose of 300-900 kcal or in a daily dose of15-45 g of protein. Such daily doses are particularly suitable forsupplemental nutrition.

To demonstrate the efficacy of a combination of PUFA, vitamin E, vitaminD and the amino acids glycine, arginine and tryptophan, an in vitrostudy can be conducted. For example, the ability of this combination torescue the atrophy induced by tumor necrosis factor-alpha (TNF-alpha) aswell as its ability to increase protein synthesis can be investigated.Increased TNF-alpha levels are connected to cancer, in particular cancercachexia, see e.g. J Gastroenterol. 2013, 48(5), 574-594 (Suzuki etal.). Suitable cells are, for example, human primary myoblasts. Linoleicacid (n-6 PUFA) and/or alpha-linolenic acid (n-3 PUFA) can, for example,be used as PUFA in the in vitro study. Possible readouts include, forexample, myotube differentiation and size (width and area), proteinsynthesis, and/or fusion index. Further possible readouts include, forexample, neuromuscular junction (acetylcholine receptor expression)and/or functionality of acetylcholine receptor measured by intracellularCa⁺⁺ rising after acetylcholine treatment.

Furthermore, the efficacy of the nutritional composition of theinvention can, for example be demonstrated using an animal model.Suitable animal models include, among others, mouse models or ratmodels. Possible readouts include, among others, grip strength and/ormuscle force. An in vivo study on cancer, in particular cancer cachexia,which involves the use of rats, is described in, e.g., J. CachexiaSarcopenia Muscle 2016, 7(1), 48-59 (Toledo et al.).

To further demonstrate the efficacy of the nutritional composition ofthe invention, a study in humans can be conducted. For example, itsefficacy on muscle protein synthesis can be investigated using aunilateral leg exercise model. Such a study involves unilateral legexercise and bilateral muscle biopsies before and after exercise. Thenutritional composition of the invention can be ingested orally, forexample shortly after exercise. Muscle protein synthesis can bequantified using ¹³C₆ phenylalanine labeling. ¹³C₆ phenylalanine can beadded to the nutritional composition of the invention, for exampleshortly before ingestion.

Preparation of Nutritional Compositions

The nutritional composition can be prepared according to methods knownin the art. For example, the nutritional composition can be prepared bymixing and homogenization. The components of the nutritional compositioncan, for example, be mixed at elevated temperatures, for example at atemperature of 50-90° C. Homogenization can, for example, be carried outat a temperature of <90° C., preferably 60-65° C., and/or at a pressureof 40-200 bar, preferably 40-110 bar, more preferably 50-100 bar.Homogenization can, for example, involve two steps (e.g., a first stepwhich can be carried out at 90-110 bar, for example 100 bar, and asecond step which can be carried out at 40-60 bar, for example 50 bar).The nutritional composition can also be sterilized. Sterilization can,for example, involve a pre-heating step (which can, e.g., be carried outat 70-100° C., preferably 85-95° C., e.g. for 2-5 minutes), a heatingstep (which can, e.g., be carried out at 130-145° C., preferably139-141° C., e.g. for 6-15 seconds) and an additional homogenizationstep (which can, e.g., be carried out at a pressure of 40-200 bar, e.g.at <90° C.).

In a preferred embodiment, the nutritional composition can, for example,be prepared by a process which comprises the following steps:

-   -   i. a first step, wherein water is provided and heated to a        temperature of 50-70° C.;    -   ii. a second step wherein, optionally, a carbohydrate        component—or a fraction thereof—and, optionally, a stabilizer,        such as MCC, is added;    -   iii. a third step, wherein the protein component is added;    -   iv. a fourth step, wherein the lipid component is added,        preferably at an elevated temperature of 80-90° C., preferably        in combination with a (further) emulsifier and/or stabilizer,        such as soy lecithin and/or diacetyl tartaric acid glycerides        (e.g. DATEM), and/or (distilled) monoglycerides;    -   v. a fifth step, wherein vitamins and, optionally, minerals and,        optionally, the remaining fraction of the carbohydrate component        and, optionally, any other powder ingredient, e.g. fibres,        aroma, and other additives, are added; at any time before,        during or after the fifth step, the mixture is allowed to cool        to 55-65° C.;    -   vi. a sixth step, wherein the pH of the mixture is adjusted to        6-9, preferably 7-8, e.g. 7;    -   vii. a seventh step, wherein the mixture is homogenized, e.g. at        60-65° C. at a pressure of 100/50 bar;    -   viii. an eighth step, wherein the mixture is sterilized; the        eighth step may comprise (8.a) a pre-heating step, (8.b) a        heating step and (8.c) an additional homogenization step.

In an alternative embodiment, all or a part of the additionalingredients, such as aroma, may be added already between the third orfourth step.

Preferably, step 8 is divided into:

-   -   a) a step 8.a, wherein the mixture is pre-heated to 70-100° C.,        preferably 85-95° C., e.g. for 2-5 minutes;    -   b) a step 8.b, wherein the mixture is heated to 130-145° C.,        preferably to 139-141° C., e.g. for 6-15 seconds; and    -   c) a step 8.c, wherein the mixture is homogenized at a pressure        of 40-200 bar; preferably step 8.c is carried out at less than        90° C.

Dose Unit and Daily Dose

The nutritional compositions herein are typically provided in a doseunit.

A dose unit herein refers to 100-200 mL, preferably 100-150 mL,preferably provided in package such as a bottle, tetra brick or bag.

Such a dose unit provides 300-500 kcal, preferably 350-450 kcal.

Such a dose unit provides 14-40 g, preferably 15-30 g, more preferably18-22 g of protein, such as 20 g of protein.

An exemplary dose unit provides 400 kcal and 20 g of protein in 125 mL.

An exemplary daily dose for complete nutrition of, e.g., 1500-2500 kcalof the nutritional compositions herein may be provided by 3-8 doseunits, preferably by 5 dose units. For example, a daily dose forcomplete nutrition may be provided by 5 dose units each providing350-450 kcal.

A typical daily dose for supplemental nutrition of, e.g., 300-900 kcalof the nutritional compositions herein may be provided by 1-3 doseunits, preferably by 1 or 2 dose units, for example by 1 or 2 dose unitseach providing 350-450 kcal.

EMBODIMENTS Embodiment 1

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients, wherein an effective amount of said active ingredientsis administered in the form of a nutritional composition comprising

-   a) a lipid component providing 40-50 EN % based on the total energy    of the nutritional composition, wherein 12-16 EN % based on the    total energy of the nutritional composition is provided by PUFA,-   b) 4.0-8.0 mg/100 mL alpha-TE vitamin E,-   c) 5.0-12.0 μg/100 mL vitamin D,-   d) 2.5-4.5 g/100 mL glycine,-   e) 0.5-1.5 g/100 mL arginine, and-   f) at least 0.02 g/100 mL tryptophan.

Embodiment 2

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to the preceding embodiment, wherein thenutritional composition has a caloric density of at least 2.0 kcal/mL,preferably at least 2.5 kcal/mL, more preferably at least 2.6 kcal/mL,even more preferably at least 2.8 kcal/mL, even more preferably at least3.0 kcal/mL, even more preferably at least 3.1 kcal/mL.

Embodiment 3

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition has a caloric density of 2.0-5.0 kcal/mL,preferably 2.5-4.0 kcal/mL, more preferably 2.6-3.8 kcal/mL, even morepreferably 2.8-3.6 kcal/mL, even more preferably 3.0-3.4 kcal/mL, evenmore preferably 3.1-3.3 kcal/mL.

Embodiment 4

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe lipid component comprises rapeseed oil and/or canola oil, preferablyrapeseed oil, also preferably canola oil.

Embodiment 5

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition comprises at least 10 wt %, preferably atleast 12 wt %, more preferably at least 13 wt % of protein based on thetotal weight of the nutritional composition.

Embodiment 6

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition comprises at least 14 g, for example 14-20g, preferably at least 15 g, for example 15-18 g, more preferably atleast 15.5 g, for example 15.5-17.0 g, most preferably at least 16 g ofprotein per 100 mL of the nutritional composition.

Embodiment 7

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component provides at least 15 EN %, for example 15-25 EN %,preferably at least 18 EN %, for example 18-22 EN %, more preferably atleast 19 EN %, for example 19-21 EN %, based on the total energy of thenutritional composition.

Embodiment 8

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein to water ratio is at least 2.0/10 [g/g], more preferably atleast 2.5/10 [g/g].

Embodiment 9

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition further comprises a carbohydrate componentproviding at least 20 EN %, preferably 30-40 EN %, more preferably 33-37EN %, for example 34-36 EN % based on the total energy of thenutritional composition.

Embodiment 10

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component provides 15-25 EN % based on the total energy ofthe nutritional composition, and wherein the nutritional compositionfurther comprises a carbohydrate component providing 30-40 EN % based onthe total energy of the nutritional composition.

Embodiment 11

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component provides 18-22 EN %, preferably 19-21 EN % basedon the total energy of the nutritional composition, the lipid componentprovides 43-47 EN %, preferably 44-46 EN % based on the total energy ofthe nutritional composition, and wherein the nutritional compositionfurther comprises a carbohydrate component providing 33-37 EN %,preferably 34-36 EN % based on the total energy of the nutritionalcomposition.

Embodiment 12

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, wherein24-32 EN % based on the total energy of the nutritional composition isprovided by MUFA, and 1-5 EN % based on the total energy of thenutritional composition is provided by SFA.

Embodiment 13

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, wherein13-15 EN % based on the total energy of the nutritional composition isprovided by PUFA, 26-30 EN %, for example 28 EN %, based on the totalenergy of the nutritional composition is provided by MUFA, and 2-4 EN %,for example 3 EN %, based on the total energy of the nutritionalcomposition is provided by SFA.

Embodiment 14

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition comprises 4.5-7.0 mg/100 mL alpha-TE vitaminE, preferably 5.0-6.5 mg/100 mL alpha-TE vitamin E, more preferably5.2-6.2 mg/100 mL alpha-TE vitamin E, even more preferably 5.5-6.0mg/100 mL alpha-TE vitamin E.

Embodiment 15

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition comprises 6.0-10.5 μg/100 mL vitamin D,preferably 7.0-9.5 μg/100 mL vitamin D, more preferably 7.2-9.0 μg/100mL vitamin D, even more preferably 7.5-8.5 μg/100 mL vitamin D.

Embodiment 16

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition further comprises proline, preferably1.5-4.0 g/100 mL proline, more preferably 2.0-3.0 g/100 mL proline, evenmore preferably 2.2-2.6 g/100 mL proline.

Embodiment 17

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition further comprises cysteine, preferably atleast 0.01 g/100 mL cysteine, more preferably 0.01-0.1 g/100 mLcysteine, even more preferably 0.02-0.05 g/100 mL cysteine.

Embodiment 18

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component comprises hydrolysed collagen.

Embodiment 19

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component comprises a protein source selected from vegetableproteins, animal proteins other than collagen and mixtures thereof, forexample milk protein, soy protein, pea protein, egg white andhydrolysates thereof.

Embodiment 20

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component comprises a protein source selected from milkproteins, such as total milk protein, milk protein isolate, milk proteinconcentrate, whey, casein and mixtures thereof.

Embodiment 21

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component comprises at least two different protein sources.

Embodiment 22

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe protein component comprises collagen hydrolysate as a first proteinsource and milk protein as a second protein source.

Embodiment 23

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition further comprises B vitamins, preferably atleast 5 mg/100 mL B vitamins, more preferably 6-20 mg/100 mL B vitamins,even more preferably 7-12 mg/100 mL B vitamins.

Embodiment 24

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition further comprises calcium, preferably 50-300mg/100 mL calcium, more preferably 120-200 mg/100 mL calcium, even morepreferably 150-175 mg/100 mL calcium.

Embodiment 25

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is an emulsion, preferably an oil-in-water(O/W) emulsion.

Embodiment 26

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition has a pH of 5.5-9.0, preferably 7.0-9.0, forexample 6-9 or 7-8.

Embodiment 27

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition has a viscosity of 50-900 mPas, preferably200-750 mPas, determined at a shear rate of γ=1 s⁻¹ at 20° C.

Embodiment 28

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is nutritionally complete.

Embodiment 29

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered orally.

Embodiment 30

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe cancer patients have a BMI of <22 kg/m2, preferably <20 kg/m2, morepreferably <18.5 kg/m2, even more preferably <17 kg/m2, if they are 70years or older, and a BMI of <20 kg/m2, preferably <18.5 kg/m2, morepreferably <17 kg/m2, even more preferably <16 kg/m2, if they areyounger than 70 years.

Embodiment 31

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe cancer patients have an FFMI of <16 kg/m2, preferably <15 kg/m2,more preferably <14 kg/m2, even more preferably <13 kg/m2, if they arefemale, and an FFMI of <18 kg/m2, preferably <17 kg/m2, more preferably<16 kg/m2, even more preferably <15 kg/m2, if they are male.

Embodiment 32

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is used in the prevention or treatment ofmalnutrition, preferably protein malnutrition, also preferablyprotein-energy malnutrition (PEM).

Embodiment 33

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is used in the prevention or treatment ofnutrient deficiencies associated with malnutrition, preferably proteinmalnutrition, also preferably protein-energy malnutrition (PEM).

Embodiment 34

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is provided in a dose unit of 100-200 mL,preferably 100-150 mL.

Embodiment 35

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is provided in a dose unit providing 300-500kcal, preferably 350-450 kcal.

Embodiment 36

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is provided in a dose unit providing 15-30g, preferably 18-22 g of protein.

Embodiment 37

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is provided in a dose unit of 125 mLproviding 400 kcal and 20 g of protein.

Embodiment 38

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in 3-8 dose units as definedin any of embodiments 34-37 daily, preferably 5 dose units daily, forexample 5 dose units daily each providing 350-450 kcal, or for example 5dose units daily each providing 18-22 g of protein.

Embodiment 39

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in 1-3 dose units as definedin any of embodiments 34-37 daily, preferably 1 or 2 dose units daily,for example 1 or 2 dose units daily each providing 350-450 kcal, or forexample 1 or 2 dose units daily each providing 18-22 g of protein.

Embodiment 40

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in a daily dose of 1500-2500kcal.

Embodiment 41

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in a daily dose of 300-900kcal.

Embodiment 42

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in a daily dose of 75-125 gof protein.

Embodiment 43

PUFA, vitamin E, vitamin D and the protein bound amino acids glycine,arginine and tryptophan as active ingredients for use in therapy ofcancer patients according to any of the preceding embodiments, whereinthe nutritional composition is administered in a daily dose of 15-45 gof protein.

Embodiment 44

Nutritional composition comprising

-   a) a lipid component providing 40-50 EN % based on the total energy    of the nutritional composition, wherein 12-16 EN % based on the    total energy of the nutritional composition is provided by PUFA,-   b) 4.0-8.0 mg/100 mL alpha-TE vitamin E,-   c) 5.0-12.0 μg/100 mL vitamin D,-   d) 2.5-4.5 g/100 mL glycine,-   e) 0.5-1.5 g/100 mL arginine, and-   f) at least 0.02 g/100 mL tryptophan.

Embodiment 45

Nutritional composition according to the preceding embodiment having acaloric density of at least 2.0 kcal/mL, preferably at least 2.5kcal/mL, more preferably at least 2.6 kcal/mL, even more preferably atleast 2.8 kcal/mL, even more preferably at least 3.0 kcal/mL, even morepreferably at least 3.1 kcal/mL.

Embodiment 46

Nutritional composition according to any of the preceding embodimentshaving a caloric density of 2.0-5.0 kcal/mL, preferably 2.5-4.0 kcal/mL,more preferably 2.6-3.8 kcal/mL, even more preferably 2.8-3.6 kcal/mL,even more preferably 3.0-3.4 kcal/mL, even more preferably 3.1-3.3kcal/mL.

Embodiment 47

Nutritional composition according to any of the preceding embodiments,wherein the lipid component comprises rapeseed oil and/or canola oil,preferably rapeseed oil, also preferably canola oil.

Embodiment 48

Nutritional composition according to any of the preceding embodimentscomprising at least 10 wt %, preferably at least 12 wt %, morepreferably at least 13 wt % of protein based on the total weight of thenutritional composition.

Embodiment 49

Nutritional composition according to any of the preceding embodimentscomprising at least 14 g, for example 14-20 g, preferably at least 15 g,for example 15-18 g, more preferably at least 15.5 g, for example15.5-17.0 g, most preferably at least 16 g of protein per 100 mL of thenutritional composition.

Embodiment 50

Nutritional composition according to any of the preceding embodiments,wherein the protein component provides at least 15 EN %, for example15-25 EN %, preferably at least 18 EN %, for example 18-22 EN %, morepreferably at least 19 EN %, for example 19-21 EN %, based on the totalenergy of the nutritional composition.

Embodiment 51

Nutritional composition according to any of the preceding embodiments,wherein the protein to water ratio is at least 2.0/10 [g/g], morepreferably at least 2.5/10 [g/g].

Embodiment 52

Nutritional composition according to any of the preceding embodimentsfurther comprising a carbohydrate component providing at least 20 EN %,preferably 30-40 EN %, more preferably 33-37 EN %, for example 34-36 EN% based on the total energy of the nutritional composition.

Embodiment 53

Nutritional composition according to any of the preceding embodiments,wherein the protein component provides 15-25 EN % based on the totalenergy of the nutritional composition, and which nutritional compositionfurther comprises a carbohydrate component providing 30-40 EN % based onthe total energy of the nutritional composition.

Embodiment 54

Nutritional composition according to any of the preceding embodiments,wherein the protein component provides 18-22 EN %, preferably 19-21 EN %based on the total energy of the nutritional composition, the lipidcomponent provides 43-47 EN %, preferably 44-46 EN % based on the totalenergy of the nutritional composition, and which nutritional compositionfurther comprises a carbohydrate component providing 33-37 EN %,preferably 34-36 EN % based on the total energy of the nutritionalcomposition.

Embodiment 55

Nutritional composition according to any of the preceding embodiments,wherein 24-32 EN % based on the total energy of the nutritionalcomposition is provided by MUFA, and 1-5 EN % based on the total energyof the nutritional composition is provided by SFA.

Embodiment 56

Nutritional composition according to any of the preceding embodiments,wherein

13-15 EN % based on the total energy of the nutritional composition isprovided by PUFA,26-30 EN %, for example 28 EN %, based on the total energy of thenutritional composition is provided by MUFA, and2-4 EN %, for example 3 EN %, based on the total energy of thenutritional composition is provided by SFA.

Embodiment 57

Nutritional composition according to any of the preceding embodimentscomprising 4.5-7.0 mg/100 mL alpha-TE vitamin E, preferably 5.0-6.5mg/100 mL alpha-TE vitamin E, more preferably 5.2-6.2 mg/100 mL alpha-TEvitamin E, even more preferably 5.5-6.0 mg/100 mL alpha-TE vitamin E.

Embodiment 58

Nutritional composition according to any of the preceding embodimentscomprising 6.0-10.5 μg/100 mL vitamin D, preferably 7.0-9.5 μg/100 mLvitamin D, more preferably 7.2-9.0 μg/100 mL vitamin D, even morepreferably 7.5-8.5 μg/100 mL vitamin D.

Embodiment 59

Nutritional composition according to any of the preceding embodimentsfurther comprising proline, preferably 1.5-4.0 g/100 mL proline, morepreferably 2.0-3.0 g/100 mL proline, even more preferably 2.2-2.6 g/100mL proline.

Embodiment 60

Nutritional composition according to any of the preceding embodimentsfurther comprising cysteine, preferably at least 0.01 g/100 mL cysteine,more preferably 0.01-0.1 g/100 mL cysteine, even more preferably0.02-0.05 g/100 mL cysteine.

Embodiment 61

Nutritional composition according to any of the preceding embodiments,wherein the protein component comprises hydrolysed collagen.

Embodiment 62

Nutritional composition according to any of the preceding embodiments,wherein the protein component comprises a protein source selected fromvegetable proteins, animal proteins other than collagen and mixturesthereof, for example milk protein, soy protein, pea protein, egg whiteand hydrolysates thereof.

Embodiment 63

Nutritional composition according to any of the preceding embodiments,wherein the protein component comprises a protein source selected frommilk proteins, such as total milk protein, milk protein isolate, milkprotein concentrate, whey, casein and mixtures thereof.

Embodiment 64

Nutritional composition according to any of the preceding embodiments,wherein the protein component comprises at least two different proteinsources.

Embodiment 65

Nutritional composition according to any of the preceding embodiments,wherein the protein component comprises collagen hydrolysate as a firstprotein source and milk protein as a second protein source.

Embodiment 66

Nutritional composition according to any of the preceding embodimentsfurther comprising B vitamins, preferably at least 5 mg/100 mL Bvitamins, more preferably 6-20 mg/100 mL B vitamins, even morepreferably 7-12 mg/100 mL B vitamins.

Embodiment 67

Nutritional composition according to any of the preceding embodimentsfurther comprising calcium, preferably 50-300 mg/100 mL calcium, morepreferably 120-200 mg/100 mL calcium, even more preferably 150-175mg/100 mL calcium.

Embodiment 68

Nutritional composition according to any of the preceding embodimentsbeing an emulsion, preferably an oil-in-water (O/W) emulsion.

Embodiment 69

Nutritional composition according to any of the preceding embodimentshaving a pH of 5.5-9.0, preferably 7.0-9.0, for example 6-9 or 7-8.

Embodiment 70

Nutritional composition according to any of the preceding embodimentshaving a viscosity of 50-900 mPas, preferably 200-750 mPas, determinedat a shear rate of γ=1 s⁻¹ at 20° C.

Embodiment 71

Nutritional composition according to any of the preceding embodimentswhich is nutritionally complete.

Embodiment 72

Dose unit comprising the nutritional composition as defined in any ofembodiments 1-71.

Embodiment 73

Dose unit according to embodiment 72 comprising 100-200 mL, preferably100-150 mL of the nutritional composition, preferably provided inpackage such as a bottle, tetra brick or bag.

Embodiment 74

Dose unit according to embodiment 72 or 73 providing 300-500 kcal,preferably 350-450 kcal.

Embodiment 75

Dose unit according to any of embodiments 72-74 providing 15-30 g,preferably 18-22 g of protein.

Embodiment 76

Dose unit according to any of embodiments 72-75 providing 400 kcal and20 g of protein in 125 mL.

Embodiment 77

Dosage regime for use in (nutritional) therapy of cancer patients,wherein a daily dose for complete nutrition is provided by 3-8 doseunits as defined in any of embodiments 72-76, preferably by 5 doseunits, for example by 5 dose units each providing 350-450 kcal.

Embodiment 78

Dosage regime according to embodiment 77, wherein the daily dose forcomplete nutrition is 1500-2500 kcal.

Embodiment 79

Dosage regime for use in (nutritional) therapy of cancer patients,wherein a daily dose for supplemental nutrition is provided by 1-3 doseunits as defined in any of embodiments 72-76, preferably by 1 or 2 doseunits, for example by 1 or 2 dose units each providing 350-450 kcal.

Embodiment 80

Dosage regime according to embodiment 79, wherein the daily dose forsupplemental nutrition is 300-900 kcal.

EXAMPLES

The nutritional composition according to Table 1 was prepared by mixingand homogenization.

Surprisingly, high caloric densities could be reached by adding collagenhydrolysate in sufficient amounts to milk protein.

The Example (Table 1) further shows that with inclusion of sufficientamounts of collagen hydrolysate very high energy densities of proteincould be reached in a formula that provides very high caloric density(3.2 kcal/mL).

The inventors further observed that fouling during heat treatment couldbe reduced/prevented when sufficient amounts of collagen hydrolysatewere used in the protein component. Advantages observed with thenutritional composition according to Table 1 include an improvedstability against subsequent UHT (no fouling), an improved viscosity andan improved shelf life (at least 6 months).

With the nutritional composition, a drinkable viscosity of anutritionally complete composition can be provided in spite of a highprotein and energy content.

The inventors further observed that bitterness of the product could bereduced by increasing wt % of collagen hydrolysate in the proteincomponent. Therefore, the nutritional composition will result in abetter patient compliance.

Trials Trials 1 and 2

The nutritional composition according to Table 1 (herein referred to as“test drink”) was given to 20 subjects with an indication forsupplemental nutrition of approx. 400 kcal per day. Subjects belong tothe age group of 65 and older. The dosage was one bottle of 125 mL perday for seven consecutive days. One such bottle provides 400 kcal,including 20 g protein (20 EN %), 20 g fat (45 EN %) and 35 gcarbohydrates (35 EN %). 14 EN % is provided by PUFA.

Adverse effects were documented. Gastrointestinal tolerance parameterswere documented. Moreover, (protein) energy intake, compliance (inparticular time until full consumption of the test drink and/or amountconsumed within 1 hour) and palatability were documented.

Trial 1

8 males and 12 females participated in the study. The test drink wasadministered in a single dose (125 mL).

All 20 subjects completed the 7 days of intervention. In total, 96% ofthe prescribed test drinks were consumed. All study participantsingested the test drink within one hour.

Gastrointestinal (GI) symptoms were comparable at baseline and at theend of the 7 day supplementation period. No severe GI symptoms wereobserved. 11 of the 20 subjects did not report any GI symptoms duringthe entire study.

The palatability assessment showed a very high acceptance of the testdrink. The majority of the subjects rated smell, taste and appearance as‘good’ at the start and at the end of the study. No rating of poor orunacceptable was observed. Furthermore, there was no appearance of tastefatigue, even though only one flavor was provided throughout the study.

The results of the palatability assessment (overall opininon) are asfollows:

Palatability Excel- Unaccept- (overall opinion) lent Good Fair Poor ableObservations Study 3 13 4 0 0 (Number of study day 1 participants) Study3 10 7 0 0 day 7

The results of the taste assessment are as follows:

Excel- Unaccept- Taste lent Good Fair Poor able Observations Study 4 124 0 0 (Number of study day 1 participants) Study 2 13 5 0 0 day 7

In conclusion, the test drink administered in a single dose waswell-accepted. The test drink showed good tolerability and palatabilityresulting in excellent compliance.

Trial 2

9 males and 11 females participated in the study. The test drink wasadministered in three doses (about 40 mL each).

All 20 subjects completed the 7 days of intervention. In total, 95% ofthe prescribed test drinks were consumed. All study participantsingested the test drink immediately after handout.

Gastrointestinal (GI) symptoms were comparable at baseline and at theend of the 7 day supplementation period. No severe GI symptoms wereobserved. 13 of the 20 subjects did not report any GI symptoms duringthe entire study.

Palatability was rated as excellent or good by the majority of thesubjects. No rating of poor or unacceptable was observed. Furthermore,there was no appearance of taste fatigue, even though only one flavorwas provided throughout the study. Perception of sweetness was rated asjust right by the majority of the subjects.

The results of the palatability assessment (overall opininon) are asfollows:

Palatability Excel- Unaccept- (overall opinion) lent Good Fair Poor ableObservations Study 3 13 4 0 0 (Number of study day 1 participants) Study1 16 3 0 0 day 7

The results of the sweetness assessment are as follows:

Ex- tremely Highly Just Slightly Not sweet Sweetness sweet Sweet rightsweet at all Observations Study 0 3 12 4 0 (Number of study day 1participants) Study 0 2 17 1 0 day 7

In conclusion, the test drink administered in three doses waswell-accepted. The test drink showed good tolerability and palatabilityresulting in excellent compliance.

Trial 3

An in vitro study is conducted to demonstrate the efficacy of acombination of PUFA, vitamin E, vitamin D and the amino acids glycine,arginine and tryptophan. The ability of this combination to rescue theatrophy induced by tumor necrosis factor-alpha (TNF-alpha) as well asits ability to increase protein synthesis is investigated. IncreasedTNF-alpha levels are connected to cancer, in particular cancer cachexia,see e.g. J Gastroenterol. 2013, 48(5), 574-594 (Suzuki et al.). Humanprimary myoblasts are used as cells. Linoleic acid (n-6 PUFA) andalpha-linolenic acid (n-3 PUFA) are used as PUFA. Readouts includemyotube differentiation and size (width and area), protein synthesis,and fusion index.

Trial 4

An in vivo study on cancer cachexia is conducted in rats to demonstratethe efficacy of the nutritional composition of the invention. Readoutsinclude grip strength and muscle force. The in vivo study is carried outin an analogous manner as described in J. Cachexia Sarcopenia Muscle2016, 7(1), 48-59 (Toledo et al.).

Trial 5

An in vivo study on muscle protein synthesis is conducted in humans todemonstrate the efficacy of the nutritional composition according toTable 1 (herein referred to as “test drink”). Its efficacy on muscleprotein synthesis is investigated using a unilateral leg exercise model.The study involves unilateral leg exercise and bilateral muscle biopsiesbefore and after exercise. The test drink is ingested orally (shortlyafter exercise). Muscle protein synthesis is quantified using ¹³C₆phenylalanine labeling. ¹³C₆ phenylalanine is added to the nutritionalcomposition of the invention (shortly before ingestion).

Methods Determination of Molecular Weight of the Hydrolysed Collagen byGPC/HPLC

Equipment: GPV/HPLC with UV detector operating at 214 nm. Column: TSK2000 SW XL (Toshoh Biosience GmbH). Isocratic elution using 400 mmol/1sodium phosphate buffer (pH 5.3). Calibration by means of well-definedType I-collagen fragments (FILK, Freiburg, Germany). The collagenhydrolysate used in the examples had an average molecular weight of 2kDa. In general, the skilled person is well aware of molecular weightdetermination via GPC. Another suitable method for determining the M_(w)of small macromolecules such as the hydrolysates described herein isMALDI-MS.

TABLE 1 Examples Protein: 20 EN % Collagen hydrolysate 80%  16 g/100 mLMilk protein 20% (Refit 10.8%/MPC-80 9.2%) glycine* 3.42 g/100 mLarginine* 1.05 g/100 mL tryptophan* 0.05 g/100 mL proline* 2.38 g/100 mLcysteine* 0.03 g/100 mL Fat: 45 EN % Rapeseed oil  16 g/100 mL of whichSFA  3 EN %  1.1 g/100 mL of which MUFA 28 EN %  9.9 g/100 mL of whichPUFA 14 EN %  5.0 g/100 mL CHO 35 EN %  28 g/100 mL Caloric density 3.2kcal/mL Water 56 mL/100 mL  FSMP balanced ** yes Vitamin D3  8 μg/100 mLVitamin E 5.67 mg/100 mL  (alpha-TE) *Bound in collagen hydrolysate ormilk protein ** Nutritionally complete in vitamins and minerals

TABLE 2 Vitamins Minimum per 100 kcal Maximum per 100 kcal Vitamin A (μgRE) 35 180 Vitamin D (μg) 0.5 3 Vitamin K (μg) 3.5 20 Vitamin C (mg) 2.222 Thiamin (mg) 0.06 0.5 Riboflavin (mg) 0.08 0.5 Vitamin B6 (mg) 0.080.5 Niacin (mg EN) 0.9 3 Folic acid (μg) 10 50 Vitamin B12 (μg) 0.07 0.7Pantothenic acid (mg) 0.15 1.5 Biotin (μg) 0.75 7.5 Vitamin E (mg α-TE)0.5 3

TABLE 3 Minerals Minimum per 100 kcal Maximum per 100 kcal Sodium (mg)30 175 Chloride (mg) 30 175 Potassium (mg) 80 295 Calcium (mg) 35 250Phosphorus (mg) 30 80 Magnesium (mg) 7.5 25 Iron (mg) 0.5 2.0 Zinc (mg)0.5 1.5 Copper (μg) 60 500 Iodine (μg) 6.5 35 Selenium (μg) 2.5 10Manganese (mg) 0.05 0.5 Chromium (μg) 1.25 15 Molybdenum (μg) 3.5 18Fluoride (mg) — 0.2

1. A method for providing nutritional therapy to cancer patients, saidmethod comprising administering a nutritional composition to said cancerpatient, said composition comprising a) a lipid component providing40-50 EN % based on the total energy of the nutritional composition,wherein 12-16 EN % based on the total energy of the nutritionalcomposition is provided by PUFA, b) 4.0-8.0 mg/100 mL alpha-TE vitaminE, c) 5.0-12.0 μg/100 mL vitamin D, d) 2.5-4.5 g/100 mL glycine, e)0.5-1.5 g/100 mL arginine, and f) at least 0.02 g/100 mL tryptophan. 2.The method of claim 1, wherein the nutritional composition has a caloricdensity of at least 2.0 kcal/mL.
 3. The method of claim 1, wherein thelipid component comprises rapeseed oil and/or canola oil.
 4. The methodof claim 1, wherein the nutritional composition comprises at least 10 wt% of protein based on the total weight of the nutritional composition.5. The method of claim 1, wherein the nutritional composition comprisesat least 14 g of protein per 100 mL of the nutritional composition. 6.The method of claim 1, wherein the protein component provides at least15 EN % based on the total energy of the nutritional composition.
 7. Adose unit comprising a nutritional composition comprising a) a lipidcomponent providing 40-50 EN % based on the total energy of thenutritional composition, wherein 12-16 EN % based on the total energy ofthe nutritional composition is provided by PUFA, b) 4.0-8.0 mg/100 mLalpha-TE vitamin E, c) 5.0-12.0 μm/100 mL vitamin D, d) 2.5-4.5 g/100 mLglycine, e) 0.5-1.5 g/100 mL arginine, and f) at least 0.02 g/100 mLtryptophan.
 8. The dose unit of claim 7, wherein wherein the nutritionalcomposition is a ready to use nutritional composition.
 9. The dose unitof claim 7, wherein dose unit is 100-200 mL, or a dose unit providing300-500 kcal, or a dose unit providing 15-30 g of protein.
 10. Themethod of claim 1, wherein the nutritional composition further comprises1.5-4.0 g/100 mL proline.
 11. The method of claim 1, wherein thenutritional composition further comprises at least 0.01 g/100 mLcysteine.
 12. The method of claim 1, wherein the protein componentcomprises hydrolysed collagen.
 13. The dose unit of claim 7, whereinsaid dose unit is 125 mL and provides 400 kcal and 20 g of protein. 14.The dose unit of claim 13, wherein said dose unit is provided in abottle, tetra brick or bag.
 15. (canceled)
 16. The dose unit of claim 7,wherein the nutritional composition is an oil-in-water (O/W) emulsion.17. The method of claim 1, wherein the nutritional composition isnutritionally complete.
 18. (canceled)
 19. The method of claim, whereinthe cancer patients have a BMI of <22 kg/m′, if they are 70 years orolder, and a BMI of <20 kg/m2, if they are younger than 70 years. 20.The method of claim 1, wherein the cancer patients have an FFMI of <16kg/m2, if they are female, and an FFMI of <18 kg/m², if they are male.21. The method of claim 7, wherein the nutritional composition isprovided in a dose unit of 100-200 mL or in a dose unit providing300-500 kcal or in a dose unit providing 15-30 g of protein.
 22. Themethod of claim 1 PUFA, vitamin E, vitamin D and the protein bound aminoacids glycine, arginine and tryptophan as active ingredients for use intherapy of cancer patients according to any of the preceding claims,wherein the nutritional composition is administered in a daily dose of1500-2500 kcal or in a daily dose of 300-900 kcal or in a daily dose of75-125 g of protein or in a daily dose of 15-45 g of protein. 23.(canceled)